Sigma receptor inhibitors

ABSTRACT

The invention relates to compounds of formula (I) having pharmacological activity towards the sigma receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which the sigma receptor is involved.

This application claims the benefit of International Application No.PCT/EP2005/009375 filed on Aug. 29, 2005 under 35 U.S.C. §371, whichclaims benefit of U.S. application Ser. No. 10/978,250, filed on Oct.29, 2004; Spanish Patent Application No. P200402441, filed on Oct. 14,2004; and European Patent Application No. 04077421.8, filed on Aug. 27,2004, each of which are incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to compounds having pharmacologicalactivity towards the sigma (σ) receptor, and more particularly to somepyrazole derivatives, to processes of preparation of such compounds, topharmaceutical compositions comprising them, and to their use in therapyand prophylaxis, in particular for the treatment of psychosis.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by better understanding of the structure of proteins and otherbiomolecules associated with target diseases. One important class ofthese proteins is the sigma (σ) receptor, a cell surface receptor of thecentral nervous system (CNS) which may be related to the dysphoric,hallucinogenic and cardiac stimulant effects of opioids. From studies ofthe biology and function of sigma receptors, evidence has been presentedthat sigma receptor ligands may be useful in the treatment of psychosisand movement disorders such as dystonia and tardive dyskinesia, andmotor disturbances associated with Huntington's chorea or Tourette'ssyndrome and in Parkinson's disease (Walker, J. M. et al,Pharmacological Reviews, 1990, 42, 355). It has been reported that theknown sigma receptor ligand rimcazole clinically shows effects in thetreatment of psychosis (Snyder, S. H., Largent, B. L. J. Neuropsychiatry1989, 1, 7). The sigma binding sites have preferential affinity for thedextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF10047, (+)cyclazocine, and (+)pentazocine and also for some narcolepticssuch as haloperidol.

The sigma receptor has at least two subtypes, which may be discriminatedby stereoselective isomers of these pharmacoactive drugs. SKF 10047 hasnanomolar affinity for the sigma 1 (σ-1) site, and has micromolaraffinity for the sigma (σ-2) site. Haloperidol has similar affinitiesfor both subtypes. Endogenous sigma ligands are not known, althoughprogesterone has been suggested to be one of them. Possiblesigma-site-mediated drug effects include modulation of glutamatereceptor function, neurotransmitter response, neuroprotection, behavior,and cognition (Quirion, R. et al. Trends Pharmacol. Sci., 1992,13:85-86). Most studies have implied that sigma binding sites(receptors) are plasmalemmal elements of the signal transductioncascade. Drugs reported to be selective sigma ligands have beenevaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad. Sci.,1996, 93:8072-8077). The existence of sigma receptors in the CNS, immuneand endocrine systems have suggested a likelihood that it may serve aslink between the three systems.

In view of the potential therapeutic applications of agonists orantagonists of the sigma receptor, a great effort has been directed tofind selective ligands. Thus, the prior art discloses different sigmareceptor ligands.

International Patent Application WO 91/09594 generically describes abroad class of sigma receptor ligands some of which are4-phenylpiperidine, -tetrahydro-pyridine or -piperazine compounds havingan optionally substituted aryl or heteroaryl, alkyl, alkenyl, alkynyl,alkoxy or alkoxyalkyl substituent on the ring N-atom. The terms aryl andheteroaryl are defined by mention of a number of such substituents.

European patent application EP 0 414 289 A1 generically discloses aclass of 1,2,3,4-tetrahydro-spiro[naphthalene-1,4′-piperidine] and1,4-dihydro-spiro[naphthalene-1,4′-piperidine] derivatives substitutedat the piperidine N-atom with a hydrocarbon group alleged to haveselective sigma receptor antagonistic activity. The term hydrocarbon, asdefined in said patent, covers all possible straight chained, cyclic,heterocyclic, etc. groups. However, only compounds having benzyl,phenethyl, cycloalkylmethyl, furyl- or thienylmethyl or lower alkyl oralkenyl as the hydrocarbon substituent at the piperidine nitrogen atomare specifically disclosed. The compounds are stated to displacetritiated di-tolyl guanidine (DTG) from sigma sites with potenciesbetter than 200 nM.1-benzyl-1,2,3,4-tetrahydro-spiro[naphthalene-1,4′-piperidine] ismentioned as a particularly preferred compound.

European patent application EP 0 445 974 A2 generically describes thecorresponding spiro[indane-1,4′-piperidine] andspiro[benzocycloheptene-5,4′-piperidine] derivatives. Again thecompounds are only stated to displace tritiated di-tolyl guanidine (DTG)from sigma sites with potencies better than 200 nM.

European patent Application EP0 431 943 A relates to a further extremelybroad class of spiropiperidine compounds substituted at the piperidineN-atom and claimed to be useful as antiarrhythmics and for impairedcardiac pump function. The said application exemplifies severalcompounds, the majority of which contain an oxo and/or a sulfonylaminosubstituent in the spiro cyclic ring system. Of the remainder compounds,the main part has another polar substituent attached to the spironucleus and/or they have some polar substituents in the substituent onthe piperidine N-atom. No suggestion or indication of effect of thecompounds on the sigma receptor is given.

Patent applications EP 518 805 A and WO 02/102387 describe sigmareceptor ligands having piperidine or spiropiperidine structures.

With regard to the chemical structure of the compounds described in thepresent patent application, there are some documents in the prior artwhich disclose pyrazole derivatives characterized, among other things,for being substituted by amino alkoxy groups in different positions ofthe pyrazole group.

U.S. Pat. No. 4,337,263 discloses 1-aryl-4-arylsulphonyl-3-aminopropoxy-1H-pyrazoles, wherein the amino group can be constituted by anN-cycle group as morpholine, piperidine or pyrrolidine group. They areused as hypolipemiant or hypocholesteroleminant agents.

Patent FR 2301250 describes similar compounds as those mentioned above,such as 1,4-diaryl-3-aminoalcoxy pyrazoles, wherein the amino groupcomprises pyrrolidine, piperidine, hydroxypiperidine, morpholine orpiperazine derivatives.

Patent Application US2003/0144309 refers to pyrazoles with their 3position substituted by a dimethylaminoethoxy group and present in their4 position a pirimidine group. They are used as inhibitors of JNK3, Lckor Src kinase activity.

International patent Application WO 02/092573 describes substitutedpirazole compounds as inhibitors of SRC and other protein kinases.

International patent Application WO 2004/017961 discloses pyrazolcompounds wherein the 3 position is substituted by an alcoxy groupdirectly bounded to a cyclic amide, which are used for therapeuticallytreating and/or preventing a sex hormone related condition in a patient.

U.S. Pat. No. 6,492,529 describes pyrazole derivatives which are usedfor the treatment of inflammatory diseases. These compounds present inthe 5 position a urea group, linked in some cases to a morpholine ethoxygroup.

International patent Application WO 04/016592 refers to pyrazolecompounds for inhibiting protein prenylation which comprises in the 5position, among others, an alcoxy group directly bonded to a cyclicamide.

However, none of these documents suggests the effect of these compoundson the sigma receptor.

There is still a need to find compounds that have pharmacologicalactivity towards the sigma receptor, being both effective and selective,and having good “drugability” properties, i.e. good pharmaceuticalproperties related to administration, distribution, metabolism andexcretion.

SUMMARY OF THE INVENTION

We have now found a family of structurally distinct pyrazol derivativeswhich are particularly selective inhibitors of the sigma receptor. Thecompounds present a pyrazol group which are characterized by thesubstitution at position 3 by an alkoxy group directly bounded to anitrogen.

In one aspect the invention is directed to a compound of the formula I:

wherein

-   -   R₁ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted arylalkyl, substituted or unsubstituted        non-aromatic heterocyclyl, substituted or unsubstituted        heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉, —CH═NR₈, —CN,        —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂,        —N═CR₈R₉, or halogen;    -   R₂ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₉, —C(O)OR₈, —C(O)NR₈R₉,        —CH═NR₈, —CN, —OR₈, —OC(O)R₉, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉,        —NO₂, —N═CR₈R₉, or halogen;    -   R₃ and R₄ are independently selected from the group formed by        hydrogen, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉, —CH═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₉, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen, or together they form a        fused ring system,    -   R₅ and R₆ are independently selected from the group formed by        hydrogen, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉, —CH═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen; together form, with the        nitrogen atom to which they are attached, a substituted or        unsubstituted heterocyclyl group;    -   n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;    -   t is 1, 2 or 3;    -   R₈ and R₉ are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted alkoxy, substituted or        unsubstituted aryloxy, or halogen;    -   or a pharmaceutically acceptable salt, isomer, prodrug or        solvate thereof.

In a second aspect the invention is directed to a compound of theformula IB:

wherein

-   -   R₁ is selected from the group formed by substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted aromatic heterocyclyl, substituted        or unsubstituted non-aromatic heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂,        —N═CR₈R₉ or halogen,    -   R₂ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;    -   R₃ and R₄ are independently selected from the group formed by        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen, or together they form a        fused ring system,    -   R₅ and R₆ are independently selected from the group formed by        hydrogen, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₈—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen; together form, with the        nitrogen atom to which they are attached, a substituted or        unsubstituted heterocyclyl group;    -   n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;    -   t is 1, 2 or 3;    -   R₈ and R₉ are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted alkoxy, substituted or        unsubstituted aryloxy, or halogen;    -   or a pharmaceutically acceptable salt, isomer, prodrug or        solvate thereof.

In one embodiment R₁ in formula I above is selected from H, —COR₈, orsubstituted or unsubstituted alkyl, preferably it is selected from H,methyl or acetyl.

In a preferred embodiment in the compound of formula (I), R₁ ishydrogen.

In another embodiment R₂ is preferably alkyl, most preferably methyl.

In another embodiment R₂ is preferably H.

In another embodiment R₁ and R₂ do not form together a fused ringsystem.

In one embodiment R₃ and R₄ are halogen or alkyl. In a more preferredembodiment they are halogen or haloalkyl.

It is preferred that the aryl substituents R₃ and R₄ are situated in themeta and/or para positions of the phenyl group.

Further, in a preferred embodiment n is preferably 2, 3, 4, 5, or 6 mostpreferably n is 2, 3 or 4. A most preferred value for n is 2.

In another preferred embodiment R₅ and R₆, together, form amorpholine-4-yl group.

In another aspect the invention is directed to a process for thepreparation of a compound of formula (I) or (IB) or a salt, isomer orsolvate thereof.

In another aspect the invention is directed to a pharmaceuticalcomposition which comprises a compound as above defined or apharmaceutically acceptable salt, enantiomer, prodrug or solvatethereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.In a further aspect the invention is directed to the use of a compoundof formula I or IB for the treatment or prophylaxis of a sigma receptormediated disease or condition.

In another preferred embodiment the compounds as above defined are usedin the manufacture of a medicament for the treatment of diarrhoea,lipoprotein disorders, migraine, obesity, arthritis, hypertension,arrhythmia, ulcer, learning, memory and attention deficits, cognitiondisorders, neurodegenerative diseases, demyelinating diseases, addictionto drugs and chemical substances including cocaine, amphetamine, ethanoland nicotine; tardive diskinesia, ischemic stroke, epilepsy, stroke,stress, cancer or psychotic conditions, in particular depression,anxiety or schizophrenia; inflammation, autoimmune diseases; or to theuse as pharmacological tool, as anxiolytic or as immunosuppressant.

In a more preferred embodiment the medicament is for the treatment ofpain, more preferably neuropathic pain or allodynia.

The above mentioned preferences and embodiments can be combined to givefurther preferred compounds or uses.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 refers to the test protocol for all tests with von Freyfilaments.

FIGS. 2 and 3 show the effect of the compound of example 1 (VII) in amodel of neuropathic pain, especially mechanical allodynia.

FIG. 2 proofs the dose dependency of the treatment with the compound ofexample 1 (VII) to show analgesia in capsaicin-induced neuropathic pain.

FIG. 3 demonstrates that the treatment with the compound of example 1(VII) is effective specifically in neuropathic pain or mechanicalallodynia as shown by the efficacy depending on the force of thevon-Frey filaments with 0.5 g being typically in the range ofneuropathic pain/allodynia.

DETAILED DESCRIPTION OF THE INVENTION

The typical compounds of this invention effectively and selectivelyinhibit the sigma receptor.

In the present description the following terms have the meaningindicated:

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting of carbon and hydrogen atoms, containing no unsaturation,having one to eight carbon atoms, and which is attached to the rest ofthe molecule by a single bond, e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals may be optionallysubstituted by one or more substituents such as a aryl, halo, hydroxy,alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro,mercapto, alkylthio, etc. If substituted by aryl we have an “Aralkyl”radical, such as benzyl and phenethyl.

“Alkenyl” refers to an alkyl radical having at least 2 C atoms andhaving one or more unsaturated bonds.

“Cycloalkyl” refers to a stable 3- to 10-membered monocyclic or bicyclicradical which is saturated or partially saturated, and which consistsolely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl.Unless otherwise stated specifically in the specification, the term“cycloalkyl” is meant to include cycloalkyl radicals which areoptionally substituted by one or more substituents such as alkyl, halo,hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.

“Aryl” refers to single and multiple ring radicals, including multiplering radicals that contain separate and/or fused aryl groups. Typicalaryl groups contain from 1 to 3 separated or fused rings and from 6 toabout 18 carbon ring atoms, such as phenyl, naphthyl, indenyl,fenanthryl or anthracyl radical. The aryl radical may be optionallysubstituted by one or more substituents such as hydroxy, mercapto, halo,alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino,aminoalkyl, acyl, alkoxycarbonyl, etc.

“Heterocyclyl” refers to a stable 3- to 15 membered ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, preferably a 4- to8-membered ring with one or more heteroatoms, more preferably a 5- or6-membered ring with one or more heteroatoms. It may be aromatic or notaromatic. For the purposes of this invention, the heterocycle may be amonocyclic, bicyclic or tricyclic ring system, which may include fusedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidised; the nitrogen atom maybe optionally quaternized; and the heterocyclyl radical may be partiallyor fully saturated or aromatic. Examples of such heterocycles include,but are not limited to, azepines, benzimidazole, benzothiazole, furan,isothiazole, imidazole, indole, piperidine, piperazine, purine,quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole,pyrazole, oxazole, isoxazole, triazole, imidazole, etc.

“Alkoxy” refers to a radical of the formula —ORa where Ra is an alkylradical as defined above, e.g., methoxy, ethoxy, propoxy, etc.

“Amino” refers to a radical of the formula-NH2, —NHRa or —NRaRb,optionally quaternized.

“Halo” or “hal” refers to bromo, chloro, iodo or fluoro.

References herein to substituted groups in the compounds of the presentinvention refer to the specified moiety that may be substituted at oneor more available positions by one or more suitable groups, e.g.,halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro;azido; alkanoyl such as a C1-6 alkanoyl group such as acyl and the like;carboxamido; alkyl groups including those groups having 1 to about 12carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3carbon atoms; alkenyl and alkynyl groups including groups having one ormore unsaturated linkages and from 2 to about 12 carbon or from 2 toabout 6 carbon atoms; alkoxy groups having one or more oxygen linkagesand from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms;aryloxy such as phenoxy; alkylthio groups including those moietieshaving one or more thioether linkages and from 1 to about 12 carbonatoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups includingthose moieties having one or more sulfinyl linkages and from 1 to about12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groupsincluding those moieties having one or more sulfonyl linkages and from 1to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkylgroups such as groups having one or more N atoms and from 1 to about 12carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6or more carbons, particularly phenyl or naphthyl and aralkyl such asbenzyl. Unless otherwise indicated, an optionally substituted group mayhave a substituent at each substitutable position of the group, and eachsubstitution is independent of the other.

Particular individual compounds of the invention falling under formula(I) include the compounds listed below:

-   Ex1 4-{2-(1-(3,4-Dichlorophenyl)-5-methyl-1H    pyrazol-3-yloxy)ethyl}morpholine (VII),-   Ex2    2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]-N,N-diethylethanamine    hydrochloride-   Ex3    1-(3,4-Dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole    hydrochloride-   Ex4    1-(3,4-Dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole    hydrochloride-   Ex5    1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperidine-   Ex6    1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole-   Ex7    3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine-   Ex8    1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-4-methylpiperazine-   Ex9 Ethyl    4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazine    carboxylate-   Ex10    1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone-   Ex11    4-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine    hydrochloride-   Ex12    1-(4-Methoxyphenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole-   Ex13    1-(4-Methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole-   Ex14    1-[2-(1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidine-   Ex15    1-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole-   Ex16    4-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}morpholine    hydrochloride-   Ex17    1-(3,4-Dichlorophenyl)-5-phenyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole    hydrochloride-   Ex18    1-(3,4-Dichlorophenyl)-5-phenyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole-   Ex19    1-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}piperidine-   Ex20    1-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole    hydrochloride-   Ex21    2-{2-[1-(3,4-dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoquinoline    hydrochloride-   Ex22    4-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}morpholine    hydrochloride-   Ex23    1-(3,4-Dichlorophenyl)-5-methyl-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole-   Ex24    1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}piperidine    hydrochloride-   Ex25    1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-4-methylpiperazine    dihydrochloride-   Ex26    1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-1H-imidazole-   Ex27    4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]-N,N-diethylbutan-1-amine-   Ex28    1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-4-phenylpiperidine    hydrochloride-   Ex29    1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-6,7-dihydro-1H-indol-4(5H)-one-   Ex30    2-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-1,2,3,4-tetrahydroisoqui-noline-   Ex31    4-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}morpholine    hydrochloride-   Ex32    2-[1-(3,4-Dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]-N,N-diethylethanamine-   Ex33    1-(3,4-Dichlorophenyl)-5-isopropyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole    hydrochloride-   Ex34    1-(3,4-Dichlorophenyl)-5-isopropyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole    hydrochloride-   Ex35    1-{2-[1-(3,4-Dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}piperidine-   Ex36    2-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoqui-noline    hydrochloride-   Ex37    4-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}morpholine-   Ex37.HCl    4-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}morpholine    hydrochloride-   Ex38    2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]N,N-diethylethanamine-   Ex38HCl    2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]N,N-diethylethanamine    hydrochloride-   Ex39    1-(3,4-dichlorophenyl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole-   Ex39HCl    1-(3,4-dichlorophenyl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole    hydrochloride-   Ex40    1-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}piperidine-   Ex40HCl    1-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}piperidine    hydrochloride-   Ex41    1-(3,4-dichlorophenyl)-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole-   Ex41HCl    1-(3,4-dichlorophenyl)-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole    hydrochloride-   Ex 42    1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazine    dihydrochloride-   Ex 43    1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine-   Ex 44    4-{2-[1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy]ethyl}morpholine-   Ex 44HCl    4-{2-[1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy]ethyl}morpholine    hydrochloride-   Ex 45    2-[1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy]-N,N-diethylethanamine    hydrochloride-   Ex 46    1-(3,4-Dichlorophenyl)-4,5-dimethyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole    hydrochloride-   Ex 47    1-(3,4-Dichlorophenyl)-4,5-dimethyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole    hydrochloride-   Ex 48    1-{2-[1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy]ethyl}piperidine-   Ex 49    4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}morpholine    hydrochloride-   Ex 50    (2S,6R)-4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}-2,6-dimethylmorpholine    hydrochloride-   Ex 51    1-{4-[1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}piperidine    hydrochloride-   Ex 52    1-(3,4-Dichlorophenyl)-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole    hydrochloride-   Ex 53    4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]-N,N-diethylbutan-1-amine    oxalate-   Ex 54    N-benzyl-4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]-N-methylbutan-1-amine    oxalate-   Ex 55    4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]-N-(2-methoxyethyl)-N-methylbutan-1-amine    oxalate-   Ex 56    4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}thiomorpholine    oxalate-   Ex 57    1-[1-(3,4-Dichlorophenyl)-5-methyl-3-(2-morpholinoethoxy)-1H-pyrazol-4-yl]ethanone    oxalate-   Ex 58    1-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazol-4-yl}ethanone    oxalate-   Ex 59    1-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(piperidin-1-yl)ethoxy]-1H-pyrazol-4-yl}ethanone    oxalate-   Ex 60    1-{1-(3,4-dichlorophenyl)-3-[2-(diethylamino)ethoxy]-5-methyl-1H-pyrazol-4-yl}ethanone    oxalate-   Ex 61    4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine-   Ex 62    N,N-Diethyl-2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethanamine-   Ex 63    1-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}piperidine    hydrochloride-   Ex 64    5-Methyl-1-(naphthalen-2-yl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole    hydrochloride    their salts, different alternative pharmaceutically acceptable    salts, solvates or prodrugs.

Unless otherwise stated, the compounds of the invention are also meantto include compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C— or ¹⁴C-enriched carbonor ¹⁵N-enriched nitrogen are within the scope of this invention.

The term “pharmaceutically acceptable salts, solvates, prodrugs” refersto any pharmaceutically acceptable salt, ester, solvate, or any othercompound which, upon administration to the recipient is capable ofproviding (directly or indirectly) a compound as described herein.However, it will be appreciated that non-pharmaceutically acceptablesalts also fall within the scope of the invention since those may beuseful in the preparation of pharmaceutically acceptable salts. Thepreparation of salts, prodrugs and derivatives can be carried out bymethods known in the art.

For instance, pharmaceutically acceptable salts of compounds providedherein are synthesized from the parent compound which contains a basicor acidic moiety by conventional chemical methods. Generally, such saltsare, for example, prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water or in an organic solvent or in a mixture of the two.Generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol or acetonitrile are preferred. Examples of the acid additionsalts include mineral acid addition salts such as, for example,hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate,and organic acid addition salts such as, for example, acetate, maleate,fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate,methanesulphonate and p-toluenesulphonate. Examples of the alkaliaddition salts include inorganic salts such as, for example, sodium,potassium, calcium, ammonium, magnesium, aluminium and lithium salts,and organic alkali salts such as, for example, ethylenediamine,ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine andbasic aminoacids salts.

Particularly favored derivatives or prodrugs are those that increase thebioavailability of the compounds of this invention when such compoundsare administered to a patient (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species.

Any compound that is a prodrug of a compound of formula (I) or (IB) iswithin the scope of the invention. The term “prodrug” is used in itsbroadest sense and encompasses those derivatives that are converted invivo to the compounds of the invention. Such derivatives would readilyoccur to those skilled in the art, and include, depending on thefunctional groups present in the molecule and without limitation, thefollowing derivatives of the present compounds: esters, amino acidesters, phosphate esters, metal salts sulfonate esters, carbamates, andamides. Examples of well known methods of producing a prodrug of a givenacting compound are known to those skilled in the art and can be founde.g. in Krogsgaard-Larsen et al. “Textbook of Drug design and Discovery”Taylor & Francis (April 2002).

The compounds of the invention may be in crystalline form either as freecompounds or as solvates and it is intended that both forms are withinthe scope of the present invention. Methods of solvation are generallyknown within the art. Suitable solvates are pharmaceutically acceptablesolvates. In a particular embodiment the solvate is a hydrate.

The compounds of formula (I) or (IB) or their salts or solvates arepreferably in pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, having apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels. Purity levels for thedrug substance are preferably above 50%, more preferably above 70%, mostpreferably above 90%. In a preferred embodiment it is above 95% of thecompound of formula (I) or (IB), or of its salts, solvates or prodrugs.

The compounds of the present invention represented by the abovedescribed formula (I) or (IB) may include enantiomers depending on thepresence of chiral centres or isomers depending on the presence ofmultiple bonds (e.g. Z, E). The single isomers, enantiomers ordiastereoisomers and mixtures thereof fall within the scope of thepresent invention.

The compounds of formula (I) or (IB) defined above can be obtained byavailable synthetic procedures similar to those described in the patentU.S. Pat. No. 4,337,263 or FR 2 472 564. For example, they can beprepared by condensing a compound of Formula (II):

in which R₁-R₄ are as defined above in formulae (I), with a compound ofFormula (III):

in which R₅, R₆ and n are as defined above in formula (I).

The reaction of compounds of formulas (II) and (III) is preferablycarried out at a temperature in the range of 60 to 120° C. in an aproticsolvent, but not limited to, such as dimethylformamide (DMF) in thepresence of an inorganic base, such as K₂CO₃.

A general scheme for synthesizing compounds (II), (I) or (IB) is:

General Scheme of Synthesis

The intermediate compound (II) can also be prepared as described in thebibliography (see L. F. Tietze et al., Synthesis, (11), 1079-1080, 1993;F. Effenberger and W. Hartmann, Chem. Ber., 102(10), 3260-3267, 1969;both cites incorporated here by reference). It can also be prepared byconventional methods, as can be seen in the synthetic examples of thepresent patent application.Compounds of Formula (III) are commercially available or can be preparedby conventional methods.

The obtained reaction products may, if desired, be purified byconventional methods, such as crystallisation and chromatography. Wherethe above described processes for the preparation of compounds of theinvention give rise to mixtures of stereoisomers, these isomers may beseparated by conventional techniques such as preparative chromatography.If there are chiral centers the compounds may be prepared in racemicform, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in pharmaceutical composition. In the case of saltsand solvates the additional ionic and solvent moieties must also benon-toxic. The compounds of the invention may present differentpolymorphic forms, it is intended that the invention encompasses allsuch forms.

Another aspect of this invention relates to a method of treating orpreventing a sigma receptor mediated disease which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound as above defined or a pharmaceuticalcomposition thereof. Among the sigma mediated diseases that can betreated are diarrhoea, lipoprotein disorders, migraine, obesity,arthritis, hypertension, arrhythmia, ulcer, cognition disorders,addiction to chemical substances such as cocaine dependency, tardivediskinesia, ischemic stroke, epilepsy, stroke, depression, stress, pain,especially neuropathic pain or allodynia, psychotic condition or cancer.The compounds of the invention can also be employed as pharmacologicaltool or as anxiolytic or immunosuppressant.

The term “pharmacological tool” refers to the property of compounds ofthe invention through which they are particularly selective ligands forSigma receptors which implies that compound of formula I, described inthis invention, can be used as a model for testing other compounds asSigma ligands, ex. a radioactive ligands being replaced, and can also beused for modeling physiological actions related to Sigma receptors.

The present invention further provides pharmaceutical compositionscomprising a compound of this invention, or a pharmaceuticallyacceptable salt, derivative, prodrug or stereoisomers thereof togetherwith a pharmaceutically acceptable carrier, adjuvant, or vehicle, foradministration to a patient.

Examples of pharmaceutical compositions include any solid (tablets,pills, capsules, granules etc.) or liquid (solutions, suspensions oremulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment the pharmaceutical compositions are in oralform, either solid or liquid. Suitable dose forms for oraladministration may be tablets, capsules, syrups or solutions and maycontain conventional excipients known in the art such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulfate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art. The tablets may for example be prepared by wet or drygranulation and optionally coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteraladministration, such as sterile solutions, suspensions or lyophilizedproducts in the appropriate unit dosage form. Adequate excipients can beused, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods suchas those described or referred to in the Spanish and US Pharmacopoeiasand similar reference texts.

Administration of the compounds or compositions of the present inventionmay be by any suitable method, such as intravenous infusion, oralpreparations, and intraperitoneal and intravenous administration. Oraladministration is preferred because of the convenience for the patientand the chronic character of the diseases to be treated.

Generally an effective administered amount of a compound of theinvention will depend on the relative efficacy of the compound chosen,the severity of the disorder being treated and the weight of thesufferer. However, active compounds will typically be administered onceor more times a day for example 1, 2, 3 or 4 times daily, with typicaltotal daily doses in the range of from 0.1 to 1000 mg/kg/day.

The compounds and compositions of this invention may be used with otherdrugs to provide a combination therapy. The other drugs may form part ofthe same composition, or be provided as a separate composition foradministration at the same time or at different time.

The following examples are given only as further illustration of theinvention, they should not be taken as a definition of the limits of theinvention.

EXAMPLES Example 1 Synthesis of 4-{2-(1-(3,4-Dichlorophenyl)-5-methyl-1Hpyrazol-3-yloxy)ethyl}morpholine (VII) Step 1: Synthesis of Acetic AcidN′-(3,4-Dichlorophenyl)hydrazide (V)

N′-(3,4-Dichlorophenyl)hydrazine was liberated from its hydrochloride(10.0 g, 46.8 mmol) by partitioning the solid between diluted Na₂CO₃solution (10 ml saturated solution and 40 ml water) and AcOEt. Theaqueous layer was extracted two more times with AcOEt, the organicextracts were dried (Na₂SO₄), the solvent was removed in vacuo, and theresidue was taken up in dry toluene (100 ml). To this solution aceticanhydride (4.78 g, 46.8 mmol) was slowly added, and the reaction mixturewas stirred at room temperature for 15 min. Light petroleum (50 ml) wasadded, the mixture was cooled in the refrigerator (−20° C.), and theresulting crystals were collected on a sintered glass funnel and washedwith cold petrol ether. Recrystallization from MeOH yielded (V) (8.30 g,81%) as shiny white crystals, mp 179-182° C. (lit. 168-171° C.). TLCCHCl₃/MeOH 9:1.

MS m/z (%): 222/220/218 (W, 3/22/34), 178 (64), 176 (100), 160 (20), 43(94).

Only the NMR signals of the dominant isomer are given (ratio ca. 9:1):

¹H-NMR (DMSO-d₆): (ppm) 9.69 (d, 11-1, NH—CO, ³J=2.0 Hz), 8.09 (d, 1H,Ph-NH, ³J=2.0 Hz), 7.32 (d, 1H, Ph 1-1-5, ³J (H5, 1-16)=8.8 Hz), 6.83(d, 1H, Ph H-2, ⁴J (H2, H6)=2.5 Hz), 6.66 (dd, 1H, Ph H-6, ⁴3(H2, 146)2.5 Hz, ³J (H5, H6)=8.8 Hz), 1.90 (s, 31-1, Me).

¹³C-NMR (DMSO-d₆): S (ppm) 169.2 (C═O), 149.6 (Ph C-1), 131.2 (Ph C-3),130.5 (Ph C-5), 119.1 (Ph C-4), 112.9 (Ph C-2*), 112.4 (Ph C-6*), 20.6(Me).

Step 2: Synthesis of 1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-ol(VI)

To a mixture of (V) (5.0 g, 22.8 mmol) and ethyl acetoacetate (2.97 g22.8 mmol) was slowly added PCl₃ (3.13 g, 22.8 mmol). The mixture waswarmed to 50° C. for 1.5 h, poured into ice water (150 ml), and theresulting precipitate was collected on a sintered glass funnel andrecrystallized from EtOH to yield (VI) (2.29 g, 41%) as white crystals,mp 208-211° C. (lit. 208-209° C.), TLC CHCl₃/MeOH 9:1.

MS m/z (%): 246/244/242 (M+, 11/59/100), 207 (32), 147 (20), 145 (34),111 (20), 109 (23), 75 (20).

¹H-NMR (CDCI3): S (ppm) 11.72 (broad s, 1H, OH), 7.54 (d, 1H, Ph H-5, 3J(H5, H6)=8.5 Hz), 7.48 (d, 1H, Ph 11-2, 4J (H2, H6)-2.5 Hz), 7.26 (dd,1H, Ph H-6, 4J (H2, H6)=2.5 Hz, 3J (H5, H6)=83 Hz), 5.63 (s, 1H, 4-H),2.28 (s, 3H, 5-Me).

¹³C-NMR (CDCl3): 6 (ppm) 163.1 (Pz C-3), 141.2 (Pz C-5), 137.9 (Ph C-1),133.1 (Ph C-3), 131.4 (Ph C-4), 131.0 (Ph C-5), 126.1 (Ph C-2), 123.6(Ph C-6), 94.5 (Pz C-4), 12.7 (5-Me).

Step 3: Synthesis of 4-{2-(1-(3,4-Dichlorophenyl)-5-methyl-1Hpyrrazol-3-yloxy)ethyl}morpholine (VII)

A mixture of (VI) (300 mg, 1.23 mmol), N-(2-chloroethyl)morpholinehydrochloride (230 mg, 123 mmol), K₂CO₃ (341 mg, 2.47 mmol), and NaI(185 mg, 1.23 mmol) in dry dimethyl formamide (5 ml) was stirredovernight at 70° C. The mixture was poured into water (20 ml), extractedfour times with Et₂O, and the organic extracts were washed withsaturated NaCl solution, dried (Na₂SO₄), and concentrated in vacuo. Theresidue was purified via MPLC (light petroleum/AcOEt 4:1) to yield (VII)(303 mg, 69%) as a colorless oil. TLC CHCl₃/MeOH 9:1.

MS m/z (%): 357/355 (Mt, 0.03/0.05), 114 (19), 113 (100), 100(92), 98(16), 56 (21).

¹H-NMR (CDCI3): S (ppm) 7.57 (d, 1H, Ph H-2, 4J (H2, H6)=2.5 Hz), 7.47(d, 1H, Ph H-5, 3J (H5, H6)_(—)8.6 Hz), 726 (dd, 1H, Ph H-6, 4.1 (H2,H6)=2.5 Hz, 3J (H5, H6)=8.6 Hz), 5.68 (s, 1H, 4-H), 4.31 (t, 2H, O—CHz,3J=5.6 Hz), 3.72 (m, 4H, Morph H-2.6), 2.77 (t, 2H, CH-Morph, 3J-5.6Hz), 2.55 (m, 411, Morph H-3.5), 2.30 (s, 3H, 5-Me).

¹³C-NMR (CDCl₃): S (ppm) 163.4 (Pz C-3), 140.5 (Pz C-5), 139.1 (Ph C-1),132.9 (Ph C-3), 130.5 (Ph C-5), 130.3 (Ph C-4), 125.7 (Ph C-2), 122.7(Ph C-6), 94.5 (Pz C-4), 66.8 (Morph C-2.6), 65.9 (O—CH2), 57.6(CH2-Morph), 53.9 (Morph C-3.5), 13.1 (5-Me).

Anal. Calcd for C16H19C12N302: C, 53.94; H, 5.38; N, 11.79. Found: C,53.85; H, 5.13; N, 11.57.

Example 22-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]-N,N-diethylethanaminehydrochloride

Beige colour amorphous solid. Yield=64%

¹H-NMR (DMSO-d₆) δ ppm: 10.0 (br s, 1H), 7.8 (d, J=1.7 Hz, 1H), 7.7 (d,J=8.7 Hz, 1H), 7.5 (dd, J=1.7 and 7.8 Hz, 1H), 5.9 (s, 1H), 4.5 (t,J=4.8 Hz, 2H), 3.45 (m, 2H), 3.2 (m, 4H), 2.3 (s, 3H), 1.2 (t, 6H)

Example 31-(3,4-Dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolehydrochloride

White-yellow solid. M.p.>280° C. (decomp.). Yield=37.5%

¹H-NMR (DMSO-d₆) δ ppm: 10.4 (br s, 1H), 7.8 (d, J=2.5 Hz, 1H), 7.7 (d,J=8.8 Hz, 1H), 7.5 (dd, J=2.5 and 8.8 Hz, 1H), 5.9 (s, 1H), 4.45 (t,J=4.7 Hz, 2H), 3.5 (m, 4H), 3.05 (m, 2H), 2.4 (s, 3H), 1.8-1.95 (m, 4H).

Example 41-(3,4-Dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazolehydrochloride

White solid. M.p.=149-155° C. Yield=51%

¹H-NMR (DMSO-d₆) δ ppm: 10.05 (br s, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.7(d, J=7.8 Hz, 1H), 7.5 (d, J=7.8 Hz, 1H), 5.8 (s, 1H), 4.2 (m, 2H), 3.5(m, 2H), 3.3 (m, 2H), 3.0 (m, 2H), 2.3 (s, 3H), 1.8-2.1 (m, 6H).

Example 51-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperidine

White solid. M.p.=119-122° C. Yield=46%

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.4 Hz, 1H), 7.5 (d, J=8.8 Hz, 1H), 7.3(dd, J=2.4 and 8.8 Hz, 1H), 5.7 (s, 1H), 4.6 (m, 2H), 2.7-3.2 (m, 4H),2.3 (s, 3H), 1.4-1.9 (m, 8H).

Example 61-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole

White solid. M.p.=111-112° C. Yield=54%

¹H-NMR (DMSO-d₆) δ ppm: 7.75 (d, J=2.3 Hz, 1H), 7.7 (d, J=8.7 Hz, 1H),7.6 (s, 1H), 7.5 (dd, J=2.3 and 8.7 Hz, 1H), 7.2 (s, 1H), 6.9 (s, 1H),5.8 (s, 1H), 4.3 (m, 4H), 2.3 (s, 3H)

Example 73-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine

White solid. M.p.=104-107° C. Yield=44%

¹H-NMR (CDCl₃) δ ppm: 8.4 (dd, J=1.3 and 4.8 Hz, 1H), 8.2 (s, 1H), 8.1(dd, J=1.3 and 8.1 Hz, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.7 Hz,1H), 7.3-7.2 (m+solvent, 2H), 5.7 (s, 1H), 4.75-4.5 (m, 3H), 3.5-3.0 (m,4H), 2.9-2.4 (m, 2H), 2.3 (m+s, 5H), 1.6 (m, 2H).

Example 81-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-4-methylpiperazine

Oil. Yield=35%

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.7 Hz, 1H), 7.3(dd, J=2.5 and 8.7 Hz, 1H), 5.7 (s, 1H), 4.3 (t, J=5.6 Hz, 2H), 2.8 (t,J=5.6 Hz, 2H), 2.7 (m, 8H), 2.4 (s, 3H), 2.3 (s, 3H).

Example 9 Ethyl4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazinecarboxylate

Oil. Yield=25%

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H),7.3-7.2 (dd+solvent, J=2.5 and 8.6 Hz, 1H), 5.7 (s, 1H), 4.4 (bm, 2H),4.15 (q, J=7.1 Hz, 2H), 3.6 (bm, 4H), 2.9-2.6 (bm, 6H), 2.3 (s, 3H),1.25 (t, J=7.1 Hz, 3H).

Example 101-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone

Oil. Yield=17%

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.3 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H),7.3-7.2 (dd+solvent, J=2.3 and 8.6 Hz, 1H), 5.7 (s, 1H), 4.4 (bm, 2H),3.6 (bm, 4H), 2.9-2.6 (bm, 6H), 2.3 (s, 3H), 2.1 (s, 3H).

Example 114-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholinehydrochloride

White solid. M.p.=169-173° C.

¹H-NMR (DMSO-d₆) δ ppm: 10.9 (br s, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.0 (d,J=8.7 Hz, 2H), 5.8 (s, 1H), 4.5 (m, 2H), 3.7-3.9 (m, 4H), 3.8 (s, 3H),3.4-3.55 (m, 4H), 3.1-3.2 (m, 2H), 2.2 (s, 3H).

Example 121-(4-Methoxyphenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole

Oil. Yield=11%

¹H-NMR (CDCl₃) δ ppm: 7.3 (d, J=8.9 Hz, 2H), 6.9 (d, J=8.9 Hz, 2H), 5.65(s, 1H), 4.3 (m, 2H), 3.8 (s, 3H), 2.9 (m, 2H), 2.65 (m, 4H), 2.2 (s,3H), 1.8 (m, 4H).

Example 131-(4-Methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole

Oil. Yield=27%

¹H-NMR (CDCl₃) δ ppm: 7.25 (d, J=8.8 Hz, 2H), 6.9 (d, J=8.8 Hz, 2H),5.55 (s, 1H), 4.15 (t, J=6.4 Hz, 2H), 3.75 (s, 3H), 2.55 (m, 6H), 2.15(s, 3H), 1.95 (m, 2H), 1.7 (m, 4H).

Example 141-[2-(1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidine

Oil. Yield=21%

¹H-NMR (CDCl₃) δ ppm: 7.25 (d, J=8.9 Hz, 2H), 6.85 (d, J=8.9 Hz, 2H),5.55 (s, 1H), 4.25 (m, 2H), 3.75 (s, 3H), 2.7 (m, 2H), 2.45 (m, 4H),2.15 (s, 3H), 1.55 (m, 4H), 1.4 (m, 2H).

Example 151-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole

Oil. Yield=31%

¹H-NMR (CDCl₃) δ ppm: 7.6 (s, 1H), 7.25 (d, J=8.7 Hz, 2H), 7.1 (s, 1H),7.0 (s, 1H), 6.9 (d, J=8.7 Hz, 2H), 5.6 (s, 1H), 4.45 (t, J=5.0 Hz, 2H),4.3 (t, J=5.0 Hz, 2H), 3.8 (s, 3H), 2.2 (s, 3H).

Example 164-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}morpholinehydrochloride

White solid. M.p.=197-207° C. Yield=52%

¹H-NMR (DMSO-d₆) δ ppm: 10.75 (br s, 1H), 7.6 (d, J=8.6 Hz, 1H), 7.5 (d,J=2.5 Hz, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 7.1 (dd, J=2.5 and 8.6 Hz, 1H),6.3 (s, 1H), 4.6 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.4-3.55 (m, 4H),3.2 (m, 2H).

Example 171-(3,4-Dichlorophenyl)-5-phenyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolehydrochloride

Yellow colour solid. M.p.=137-147° C. Yield=52%

¹H-NMR (DMSO-d₆) δ ppm: 10.35 (br s, 1H), 7.6 (d, J=8.7 Hz, 1H), 7.5 (d,J=2.5 Hz, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 7.1 (dd, J=2.5 and 8.7 Hz, 1H),6.3 (s, 1H), 4.5 (m, 2H), 3.6 (m, 4H), 3.1 (m, 2H), 1.85-2.0 (m, 4H).

Example 181-(3,4-Dichlorophenyl)-5-phenyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole

Oil. Yield=63%

¹H-NMR (CDCl₃) δ ppm: 7.5 (d, J=2.4 Hz, 1H), 7.3 (m, 3H), 7.25 (m, 3H),6.95 (dd, J=2.4 and 8.6 Hz, 1H), 5.95 (s, 1H), 4.3 (t, J=6.4 Hz, 2H),2.45-2.75 (m, 6H), 2.05 (m, 2H), 1.8 (m, 4H).

Example 191-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}piperidine

Oil. Yield=44%

¹H-NMR (CDCl₃) δ ppm: 7.45 (d, J=2.5 Hz, 1H), 7.35 (m, 3H), 7.2 (m, 3H),6.95 (dd, J=2.5 and 8.6 Hz, 1H), 6.0 (s, 1H), 4.4 (m, 2H), 2.8 (m, 2H),2.5 (m, 4H), 1.4-1.7 (m, 6H).

Example 201-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazolehydrochloride

Beige colour solid. M.p.=147-155° C. Yield=44%

¹H-NMR (DMSO-d₆) δ ppm: 9.2 (s, 1H), 7.8 (s, 1H), 7.7 (s, 1H), 7.6 (d,J=8.6 Hz, 1H), 7.5 (d, J=2.4 Hz, 1H), 7.4 (m, 3H), 7.25 (m, 2H), 7.05(dd, J=2.4 and 8.6 Hz, 1H), 6.2 (s, 1H), 4.6 (m, 4H)

Example 212-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoquinolinehydrochloride

White solid. M.p.=185-189° C. Yield=34%

¹H-NMR (CDCl₃) δ ppm: 13.5 (bs, 1H), 7.4-7.2 (m, 10H), 7.1 (d, J=6.7 Hz,1H), 6.95 (dd, J=2.5 and 8.6 Hz, 1H), 6.0 (s, 1H), 4.9 (s, 2H), 4.7 (d,J=14 Hz, 1H), 4.25 (dd, J=5.4 and 5.8 Hz, 1H), 3.8 (m, 1H), 3.6-3.4 (m,4H), 3.1 (m, 1H).

Example 224-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}morpholinehydrochloride

Beige colour solid. M.p.=150-154° C. Yield=28%

¹H-NMR (DMSO-d₆) δ ppm: 10.4 (br s, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.7 (d,J=8.8 Hz, 1H), 7.5 (dd, J=2.5 ans 8.8 Hz, 1H), 5.8 (s, 1H), 4.1 (t,J=5.9 Hz, 2H), 3.6-3.9 (m, 4H), 3.4 (m, 2H), 3.0-3.15 (m, 4H), 2.3 (s,3H), 1.8-1.7 (m, 4H).

Example 231-(3,4-Dichlorophenyl)-5-methyl-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole

Oil. Yield=46%

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H), 7.3(dd, J=2.5 and 8.6 Hz, 1H), 5.65 (s, 1H), 4.15 (t, J=6.3 Hz, 2H), 2.6(m, 6H), 2.3 (s, 3H), 1.8 (m, 8H).

Example 24 Synthesis of1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}piperidinehydrochloride Synthesis of3-(4-chlorobutoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole (SchemeI, step 3A.)

A mixture of 1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-ol, obtainedin step 2 of Example 1 (1.67 g, 6.87 mmol), 1-bromo-4-chlorobutane (1.58ml, 13.74 mmol), 1K₂CO₃ (2.85 g, 20.6 mmol) and NaI (1.03 g, 6.87 mmol)in dry dimethylformamide (100 ml) was stirred overnight at roomtemperature. Solvent was evaporated in vacuo and the crude residue waspartitioned between water/dichloromethane. The organic extracts werewashed with saturated NaCl solution, dried on Na₂SO₄ and concentrated invacuo to obtain 2.07 g (90%) of an oily compound, corresponding to3-(4-chlorobutoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole, whichsolidifies on standing.

¹H-NMR (CDCl₃) δ ppm: 7.6 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H), 7.3(dd, J=2.5 and 8.6 Hz, 1H), 5.65 (s, 1H), 4.2 (t, J=5.8 Hz, 2H), 3.6 (t,J=6.2 Hz, 2H), 2.3 (s, 3H), 1.95 (m, 4H).

Synthesis of1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}piperidinehydrochloride (Scheme I, step 4A)

A mixture of3-(4-chlorobutoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole (0.1 g,0.3 mmol), piperidine (29.5 μl, 0.3 mmol), K₂CO₃ (124 mg, 0.9 mmol) andNaI (45 mg, 0.3 mmol) in dry dimethylformamide (5 ml) and toluene (5 ml)was refluxed overnight. Solvents were evaporated in vacuo and the cruderesidue partitioned in water/ethylic ether. The organic extracts werewashed with saturated NaCl solution, dried on Na₂SO₄ and concentrated invacuo to obtain a crude oil, which was purified by column chromatographyon silica gel (ethyl acetate/methanol 9:1).

1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}piperidine,obtained as an oil, was dissolved in ethanol saturated with HCl gas andcrystallized. A white solid corresponding to its hydrochloride salt wasobtained.

Thus1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}piperidinehydrochloride

White solid. M.p.=156-161° C. Yield=32%

¹H-NMR (CH₃OH-d₄) δ ppm: 7.7 (d, J=2.5 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H),7.4 (dd, J=2.5 and 8.7 Hz, 1H), 5.8 (s, 1H), 4.2 (t, J=5.7 Hz, 2H), 3.5(m, 2H), 3.2 (m, 2H), 2.9 (m, 2H), 2.35 (s, 3H), 1.95-1.5 (m, 10H).

Example 251-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-4-methylpiperazinedihydrochloride

White solid. M.p.=18°-185° C. Yield=32%

¹H-NMR (DMSO-d₆) δ ppm: 11.7 (br s, 2H), 7.8 (d, J=2.5 Hz, 1H), 7.7 (d,J=8.8 Hz, 1H), 7.5 (dd, J=2.5 and 8.8 Hz, 1H), 5.8 (s, 1H), 4.1 (t, J=6Hz, 2H), 3.75-3.15 (m, 10H), 2.8 (s, 3H), 2.3 (s, 3H), 1.8-1.7 (m, 4H).

Example 261-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-1H-imidazole

Oil. Yield=30%

¹H-NMR (CDCl₃) δ ppm: 7.6 (s, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.5 (d, J=8.7Hz, 1H), 7.3 (dd, J=2.3 and 8.7 Hz, 1H), 7.1 (s, 1H), 6.95 (s, 1H), 5.65(s, 1H), 4.2 (t, J=6.2 Hz, 2H), 4.05 (t, J=7.2 Hz, 2H), 2.3 (s, 3H), 2.0(m, 2H), 1.8 (m, 2H).

Example 274-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]-N,N-diethylbutan-1-amine

Oil. Yield=39%.

¹H-NMR (CDCl₃) δ ppm: 7.5 (d, J=2.5 Hz, 1H), 7.4 (d, J=8.6 Hz, 1H), 7.2(dd, J=2.5 and 8.6 Hz, 1H), 5.6 (s, 1H), 4.1 (t, J=6.2 Hz, 2H), 2.5 (m,6H), 2.25 (s, 3H), 1.7-1.55 (m, 4H), 1.0 (t, J=6.4 Hz, 6H).

Example 281-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-4-phenylpiperidinehydrochloride

White solid. M.p.=166-170° C. Yield=37%

¹H-NMR (DMSO-d₆) δ ppm: 9.8 (br s, 1H), 7.8 (d, J=2.4 Hz, 1H), 7.7 (d,J=8.8 Hz, 1H), 7.5 (dd, J=2.4 and 8.8 Hz, 1H), 7.35-7.2 (m, 5H), 5.8 (s,1H), 4.1 (t, J=5.8 Hz, 2H), 3.5 (d, J=11.6 Hz, 2H), 3.1-3.0 (m, 4H), 2.8(m, 1H), 2.3 (s, 3H), 2.0-1.75 (m, 8H).

Example 291-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-6,7-dihydro-1H-indol-4(5H)-one

Oil. Yield=13%

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.3 Hz, 1H), 7.5 (d, J=8.7 Hz, 1H),7.25 (dd+solvent, J=2.3 and 8.7 Hz, 1H), 6.6 (d, J=2.9 Hz, 1H), 6.55 (d,J=2.2 Hz, 1H), 5.6 (s, 1H), 4.2 (t, J=6.0 Hz, 2H), 3.9 (t, J=7.0 Hz,2H), 2.75 (t, J=6.2 Hz, 2H), 2.45 (t, J=6.4 Hz, 2H), 2.3 (s, 3H), 2.15(m, 2H), 1.9-1.7 (m, 4H).

Example 302-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-1,2,3,4-tetrahydroisoquinoline

Oil. Yield=61%

¹H-NMR (CDCl₃) δ ppm: 7.5 (d, J=2.2 Hz, 1H), 7.4 (d, J=8.7 Hz, 1H), 7.2(dd+solvent, J=2.2 and 8.7 Hz, 1H), 7.05 (m, 3H), 6.95 (m, 1H), 5.6 (s,1H), 4.2 (m, 2H), 3.6 (m, 2H), 2.9-2.7 (m, 4H), 2.6 (m, 2H), 2.25 (s,3H), 1.8 (m, 4H).

Example 314-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}morpholinehydrochloride

White solid. M.p.=195-197° C. Yield=47%

¹H-NMR (DMSO-d₆) δ ppm: 10.5 (br s, 1H), 7.75 (2 d, J=2.5 and 8.6 Hz,2H), 7.45 (dd, J=2.5 and 8.6 Hz, 1H), 5.9 (s, 1H), 4.5 (bs, 2H), 3.95(m, 2H), 3.75 (t, J=11.7 Hz, 2H), 3.5 (m, 4H), 3.15 (m, 2H), 3.0 (sep,J=6.9 Hz, 1H), 1.1 (d, J=6.9 Hz, 6H).

Example 322-[1-(3,4-Dichlorophenyl)-isopropyl-1H-pyrazol-3-yloxy]-N,N-diethylethanamine

Oil. Yield=32%

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.3 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H),7.25 (dd, J=2.3 and 8.6 Hz, 1H), 5.7 (s, 1H), 4.3 (t, J=5.8 Hz, 2H), 3.0(m, 3H), 2.7 (m, 4H), 1.2 (d, J=6.9 Hz, 6H), 1.1 (t, J=7.1 Hz, 6H)

Example 331-(3,4-Dichlorophenyl)-5-isopropyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolehydrochloride

White solid. M.p.=138-142° C. Yield=17%

¹H-NMR (DMSO-d₆) δ ppm: 10.15 (br s, 1H), 7.8 (m, 2H), 7.45 (dd, J=2.4and 8.7 Hz, 1H), 5.9 (s, 1H), 4.4 (t, J=4.6 Hz, 2H), 3.5 (m, 4H), 3.05(m, 3H), 2.0-1.8 (m, 4H), 1.1 (d, J=6.7 Hz, 6H).

Example 341-(3,4-Dichlorophenyl)-5-isopropyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazolehydrochloride

White solid. M.p.=152-156° C. Yield=29%

¹H-NMR (DMSO-d₆) δ ppm: 10.2 (br s, 1H), 7.75 (m, 2H), 7.45 (dd, J=2.4and 8.7 Hz, 1H), 5.85 (s, 1H), 4.15 (t, J=6.0 Hz, 2H), 3.5 (m, 2H), 3.2(m, 2H), 3.0 (m, 3H), 2.1-1.8 (m, 6H), 1.1 (d, J=6.7 Hz, 6H).

Example 351-{2-[1-(3,4-Dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}piperidine

Oil. Yield=42%

¹H-NMR (CDCl₃) δ ppm: 7.5 (d, J=2.4 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.3(m, 1H), 5.7 (s, 1H), 4.3 (t, J=5.7 Hz, 2H), 2.95 (sep, J=6.7 Hz, 1H),2.8 (m, 2H), 2.5 (m, 4H), 1.6 (m, 4H), 1.45 (m, 2H), 1.15 (d, J=6.7 Hz,6H).

Example 362-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoquinolinehydrochloride

White solid. M.p.=186-191° C. Yield=33%.

¹H-NMR (CDCl₃) δ ppm: 13.4 (bs, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.5 (d,J=2.3 Hz, 1H), 7.3-7.15 (m, 4H), 7.1 (d, J=7.0 Hz, 1H), 5.7 (s, 1H), 4.8(t, J=4.4 Hz, 2H), 4.65 (dd, J=12.8 and 3 Hz, 1H), 4.25 (dd, J=5.5 and15.8 Hz, 1H), 3.8-3.7 (m, 1H), 3.6-3.4 (m, 4H), 3.15-3.05 (m, 1H), 2.95(sep, J=6.7 Hz, 1H), 1.2 (d, J=6.7 Hz, 6H).

Example 37 Synthesis of4-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}morpholine SchemeI, step 1: Synthesis of 1-(3,4-dichlorophenyl)-1H-pyrazol-3-ol

N′-(3,4-Dichlorophenyl)hydrazine was liberated from its hydrochloride(8.7 g, 40.6 mmol) by partitioning the solid between dilutes Na₂CO₃solution and ethyl acetate. The aqueous layer was extracted 2 more timeswith AcOEt, dried over Na₂SO₄ and the solvent removed in vacuo. Theresidue is taken up in t-butyl alcohol (60 ml) and, in a dry nitrogenatmosphere, the ethyle propionate (4.6 ml, 44.66 mmol) was dropwiseadded. The mixture was ice-cooled and potassium t-butoxide (10.5 g, 81.2mmol) was slowly added over the time of 1 hr. The resulting mixture wasstirred overnight at room temperature. The solvent was evaporated invacuo and ice-water was added. The resulting aqueous solution isextracted with dichloromethane and acidified to pH 6 with acetic acid.The solid precipitated was filtered off, dried and crystallized fromethyl acetate yielding 2.4 g of brown solid. The mother liquors wereevaporated to dryness and the crude residue was column chromatographedon silica gel (petroleum ether/AcOEt 9:1) another fraction of 1 g wasobtained (total yield 37%)

¹H-NMR (CDCl₃) δ ppm: 7.65 (d, J=2.7 Hz, 1H), 7.6 (d, J=2.5 Hz, 1H), 7.5(d, J=8.8 Hz, 1H), 7.35 (dd, J=2.5 and 8.8 Hz, 1H), 5.95 (d, J=2.7 Hz,1H).

Synthesis of4-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}morpholine (SchemeI, step 2B.)

The compound was obtained starting from1-(3,4-dichlorophenyl)-1H-pyrazol-3-ol and N-(2-chloroethyl)morpholinehydrochloride using the same synthetic procedure described in Step 3 ofExample 1.

Thus 4-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}morpholine

Oil. Yield=78%

¹H-NMR (CDCl₃) δ ppm: 7.7 (d, J=2.4 Hz, 1H), 7.65 (d, J=2.7 Hz, 1H), 7.4(m, 2H), 5.95 (d, J=2.7 Hz, 1H), 4.4 (m, 2H), 3.75 (m, 4H), 2.8 (m, 2H),2.6 (m, 4H).

Hydrochloride salt: white solid. M.p.=162-166° C.

Example 382-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]N,N-diethylethanamine

Oil. Yield=53%

¹H-NMR (CDCl₃) δ ppm: 7.75 (d, J=2.2 Hz, 1H), 7.65 (d, J=2.7 Hz, 1H),7.4 (m, 2H), 5.9 (d, J=2.7 Hz, 1H), 4.3 (t, J=6.2 Hz, 2H), 2.9 (t, J=6.2Hz, 2H), 2.65 (q, J=7.1 Hz, 4H), 1.1 (t, J=7.1 Hz, 6H).

Hydrochloride salt: white solid. M.p.=142-151° C.

Example 391-(3,4-dichlorophenyl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole

Oil. Yield=45%

¹H-NMR (CDCl₃) δ ppm: 7.7 (d, J=2.0 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.4(m, 2H), 5.95 (d, J=2.7 Hz, 1H), 4.4 (t, J=5.8 Hz, 2H), 2.9 (t, J=5.8Hz, 2H), 2.65 (m, 4H), 1.8 (m, 4H).

Hydrochloride salt: White solid. M.p.=172-176° C.

Example 401-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}piperidine

Oil. Yield=57%

¹H-NMR (CDCl₃) δ ppm: 7.75 (d, J=2.1 Hz, 1H), 7.65 (d, J=2.6 Hz, 1H),7.4 (m, 2H), 5.9 (d, J=2.5 Hz, 1H), 4.4 (t, J=5.5 Hz, 2H), 2.8 (m, 2H),2.5 (m, 4H), 1.7-1.4 (m, 6H).

Hydrochloride salt: white solid. M.p.=172-177° C.

Example 411-(3,4-dichlorophenyl)-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole

Oil. Yield=51%

¹H-NMR (CDCl₃) δ ppm: 7.7 (d, J=2.1 Hz, 1H), 7.6 (d, J=2.6 Hz, 1H), 7.35(m, 2H), 5.85 (d, J=2.6 Hz, 1H), 4.2 (t, J=6.3 Hz, 2H), 2.65 (t, J=7.6Hz, 2H), 2.55 (m, 4H), 2.05-1.75 (m, 6H).

Hydrochloride salt: beige colour solid. M.p.=156-159° C.

¹H-NMR (CDCl₃) δ ppm: 12.7 (bs, 1H), 7.7 (2d, J=2.5 and 2.6 Hz, 2H),7.5-7.4 (m, 2H), 5.9 (d, J=2.6 Hz, 1H), 4.35 (t, J=5.7 Hz, 2H), 3.8 (m,2H), 3.3 (m, 2H), 2.8 (m, 2H), 2.45 (m, 2H), 2.25 (m, 2H), 2.05 (m, 2H).

Example 421-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazinedihydrochloride

White solid. Yield=60%

¹H-NMR (DMSO-d₆+TFAA) δ ppm: 9.1 (br s, 1H), 7.7 (d, J=2.3 Hz, 1H), 7.6(d, J=8.7 Hz, 1H), 7.4 (dd, J=2.3 and 8.7 Hz, 1H), 5.8 (s, 1H), 4.45 (m,2H), 3.6-3.2 (m, 10H), 2.3 (s, 3H).

Example 431-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine

Oil. Yield=45%

¹H-NMR (DMSO-d₆) δ ppm: 7.75 (d, J=2.5 Hz, 1H), 7.7 (d, J=8.7 Hz, 1H),7.5 (dd, J=2.5 and 8.7 Hz, 1H), 5.8 (s, 1H), 4.15 (t, J=5.7 Hz, 2H), 2.7(t, J=5.7 Hz, 2H), 2.65-2.5 (m, 4H), 2.3 (s, 3H), 2.2 (m, 1H), 1.95 (m,1H), 1.35 (m, 1H).

Example 444-(2-(1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)ethyl)morpholine

Oil. Yield=76%

¹H-NMR (DMSO-d₆) δ ppm: 7.7 (d, J=2.5 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H),7.45 (dd, J=2.5 and 8.8 Hz, 1H), 4.25 (t, J=5.7 Hz, 2H), 3.55 (t, J=4.7Hz, 4H), 2.65 (t, J=5.7 Hz, 2H), 2.4 (t, J=4.7 Hz, 4H), 2.25 (s, 3H),1.8 (s, 3H).

Hydrochloride salt: white solid. M.p.=175-179° C.

Example 452-(1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)-N,N-diethylethanaminehydrochloride

White solid. Yield=40%. M.p.=134-136° C.

¹H-NMR (DMSO-d₆+TFAA) δ ppm: 9.4 (br s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.6(d, J=8.7 Hz, 1H), 7.4 (dd, J=2.5 and 8.7 Hz, 1H), 4.45 (t, J=5.0 Hz,2H), 3.5 (m, 2H), 3.15 (m, 4H), 2.2 (s, 3H), 1.8 (s, 3H), 1.2 (t, J=7.0Hz, 6H).

Example 461-(3,4-dichlorophenyl)-4,5-dimethyl-3-(2-(pyrrolidin-1-yl)ethoxy)-1H-pyrazolehydrochloride

Beige solid. Yield=31%. M.p.=146-148° C.

¹H-NMR (DMSO-d₆) δ ppm: 10.3 (br s, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.7 (d,J=8.8 Hz, 1H), 7.5 (dd, J=2.5 and 8.8 Hz, 1H), 4.5 (t, J=4.8 Hz, 2H),3.55 (m, 4H), 3.15-3.05 (m, 2H), 2.25 (s, 3H), 2.05-1.95 (m, 2H), 1.85(s+m, 5H).

Example 471-(3,4-dichlorophenyl)-4,5-dimethyl-3-(3-(pyrrolidin-1-yl)propoxy)-1H-pyrazolehydrochloride

Beige solid. Yield=63%. M.p.=155-157° C.

¹H-NMR (DMSO-d₆+TFAA) δ ppm: 9.5 (br s, 1H), 7.6 (d, J=2.5 Hz, 1H), 7.55(d, J=8.7 Hz, 1H), 7.35 (dd, J=2.5 and 8.7 Hz, 1H), 4.2 (t, J=5.8 Hz,2H), 3.5 (m, 2H), 3.2 (m, 2H), 2.9 (m, 2H), 2.15 (s, 3H), 2.1 (m, 2H),1.9 (m, 2H), 1.85-1.75 (m+s, 5H).

Example 481-(2-(1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)ethyl)piperidine

Beige solid. MP 64-67° C.

¹H-NMR (DMSO-d₆) δ ppm: 7.75 (d, J=2.4 Hz, 1H), 7.7 (d, J=8.8 Hz, 1H),7.45 (dd, J=2.4 and 8.8 Hz, 1H), 4.25 (t, J=5.6 Hz, 2H), 2.65 (m, 2H),2.4 (m, 4H), 2.25 (s, 3H), 1.8 (s, 3H), 1.5-1.35 (m, 6H).

Example 494-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}morpholinehydrochloride

White solid. M.p.=165-169° C. Yield=66%

¹H-NMR (CDCl₃) δ ppm: 13.1 (br s, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.7 (d,J=2.6 Hz, 1H), 7.5 (d, J=8.8 Hz, 1H), 7.4 (dd, J=2.4 and 8.8 Hz, 1H),5.9 (d, J=2.6 Hz, 1H), 4.3 (m, 4H), 4.0 (m, 2H), 3.45 (m, 2H), 3.05 (m,2H), 2.9-2.8 (m, 2H), 2.15 (m, 2H), 1.9 (m, 2H).

Example 50(2S,6R)-4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}-2,6-dimethylmorpholinehydrochloride

White solid. M.p.=149-154° C. Yield=36%

¹H-NMR (CDCl₃) δ ppm: 13.0 (br s, 1H), 7.75 (d, J=2.3 Hz, 1H), 7.7 (d,J=2.6 Hz, 1H), 7.5-7.4 (m, 2H), 5.9 (d, J=2.6 Hz, 1H), 4.4 (m, 2H), 4.3(t, J=5.8 Hz, 2H), 3.35 (d, J=11.5 Hz, 2H), 3.05 (m, 2H), 2.35 (q,J=10.8 Hz, 2H), 2.15 (m, 2H), 1.9 (m, 2H), 1.2 (d, J=6.3 Hz, 6H).

Example 511-{4-[1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}piperidinehydrochloride

White solid. m.p.=156-161° C. Yield 25%

¹H-NMR (CDCl₃) δ ppm: 12.2 (br s, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.7 (d,J=2.6 Hz, 1H), 7.5-7.4 (m, 2H), 5.9 (d, J=2.6 Hz, 1H), 4.3 (t, J=5.8 Hz,2H), 3.55 (d, J=11 Hz, 2H), 3.0 (m, 2H), 2.6 (q, J=9.5 Hz, 2H), 2.35 (q,J=12.6 Hz, 2H), 2.15 (m, 2H), 1.9-1.8 (m, 5H), 1.4 (m, 1H).

Example 521-(3,4-Dichlorophenyl)-3-(4-[pyrrolidin-1-yl]butoxy)-1H-pyrazolehydrochloride

White solid. M.p.=181-186° C. Yield=30%

¹H-NMR (CDCl₃) δ ppm: 12.4 (br s, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.7 (d,J=2.6 Hz, 1H), 7.5-7.4 (m, 2H), 5.9 (d, J=2.6 Hz, 1H), 4.25 (t, J=5.9Hz, 2H), 3.8 (m, 2H), 3.1 (m, 2H), 2.8 (m, 2H), 2.3-1.9 (m, 8H).

Example 534-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]-N,N-diethylbutan-1-amineoxalate

White solid. M.p.=130-135° C. Yield=22%

¹H-NMR (CD₃OD) δ ppm: 8.1 (d, J=2.5 Hz, 1H), 7.9 (d, J=2.2 Hz, 1H), 7.6(m, 2H), 6.0 (d, J=2.4 Hz, 1H), 4.35 (m, 2H), 3.25 (q, J=7.1 Hz, 6H),1.9 (m, 4H), 1.35 (t, J=7.1 Hz, 6H).

Example 54N-benzyl-4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]-N-methylbutan-1-amineoxalate

White solid. M.p.=141-143° C. Yield=37%

¹H-NMR (CD₃OD) δ ppm: 8.1 (d, J=2.6 Hz, 1H), 7.9 (d, J=2.4 Hz, 1H), 7.6(m, 2H), 7.5 (m, 5H), 6.0 (d, J=2.6 Hz, 1H), 4.35 (s, 2H), 4.3 (t, J=5.7Hz, 2H), 3.25 (m, 2H), 2.8 (s, 3H), 1.9 (m, 4H).

Example 554-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]-N-(2-methoxyethyl)-N-methylbutan-1-amineoxalate

White solid. Yield=56%. M.p.=97-100° C.

¹H-NMR (CD₃OD) δ ppm: 8.1 (d, J=2.6 Hz, 1H), 7.9 (d, J=2.2 Hz, 1H), 7.6(m, 2H), 6.0 (d, J=2.6 Hz, 1H), 4.35 (t, J=5.7 Hz, 2H), 3.7 (t, J=5.0Hz, 2H), 3.4 (s, 3H), 3.4-3.2 (m, 4H), 2.9 (s, 3H), 1.9 (m, 4H).

Example 564-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}thiomorpholineoxalate

White solid. Yield=66%. M.p.=175-177° C.

¹H-NMR (DMSO-d₆) δ ppm: 8.4 (d, J=2.7 Hz, 1H), 8.0 (d, J=2.2 Hz, 1H),7.7 (m, 2H), 6.05 (d, J=2.6 Hz, 1H), 4.2 (m, 2H), 3.1 (m, 4H), 2.85-2.75(m, 6H), 1.7 (m, 4H).

Example 571-[1-(3,4-Dichlorophenyl)-5-methyl-3-(2-morpholinoethoxy)-1H-pyrazol-4-yl]ethanoneoxalate

White solid. Yield=74%. M.p.=188-192° C.

¹H-NMR (DMSO-d₆) δ ppm: 7.85 (d, J=2.5 Hz, 1H), 7.8 (d, J=8.6 Hz, 1H),7.55 (dd, J=2.5 and 8.6 Hz, 1H), 4.35 (m, 2H), 3.6 (m, 4H), 2.9 (m, 2H),2.65 (m, 4H), 2.5 (s, 3H), 2.4 (s, 3H).

Example 581-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazol-4-yl}ethanoneoxalate

White solid. Yield=58%. M.p.=159-162° C.

¹H-NMR (CD₃OD) δ ppm: 7.75 (2d, J=1.6 y 8.5 Hz, 2H), 7.45 (dd, J=1.6 y8.5 Hz, 1H), 4.65 (t, J=5.0 Hz 2H), 3.65 (t, J=5.0 Hz, 2H), 3.5 (m, 4H),2.55 (s, 3H), 2.50 (s, 3H), 2.15 (m, 4H).

Example 591-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(piperidin-1-yl)ethoxy]-1H-pyrazol-4-yl}ethanoneoxalate

White solid. Yield=81%. M.p.=158-161° C.

¹H-NMR (DMSO-d₆) δ ppm: 7.85 (d, J=2.3 Hz, 1H), 7.8 (d, J=8.6 Hz, 1H),7.55 (dd, J=2.3 and 8.6 Hz, 1H), 4.5 (m, 2H), 3.25 (m, 2H), 3.0 (m, 4H),2.5 (s, 3H), 2.4 (s, 3H), 1.7 (m, 4H), 1.5 (m, 2H).

Example 601-{1-(3,4-dichlorophenyl)-3-[2-(diethylamino)ethoxy]-5-methyl-1H-pyrazol-4-yl}ethanoneoxalate

White solid. Yield=75%. M.p.=147-149° C.

¹H-NMR (DMSO-d₆) δ ppm: 7.85 (d, J=2.3 Hz, 1H), 7.8 (d, J=8.6 Hz, 1H),7.55 (dd, J=2.3 and 8.6 Hz, 1H), 4.45 (t, J=5.2 Hz, 2H), 3.3 (m, 2H),3.0 (q, J=8.0 Hz, 4H), 2.5 (s, 3H), 2.4 (s, 3H), 1.15 (t, J=8.0 Hz, 6H).

Example 614-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine

Oil. Yield=45%

¹H-NMR (CDCl₃) δ ppm: 7.9-7.8 (m, 4H), 7.6-7.5 (m, 3H), 5.7 (s, 1H), 4.4(m, 2H), 3.8 (m, 4H), 2.85 (m, 2H), 2.65 (m, 4H), 2.35 (s, 3H).

Example 62N,N-Diethyl-2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethanamine

Oil. Yield=27%

¹H-NMR (CDCl₃) δ ppm: 8.0-7.8 (m, 4H), 7.6-7.5 (m, 3H), 5.7 (s, 1H), 4.4(m, 2H), 3.05 (m, 2H), 2.8 (m, 4H), 2.35 (s, 3H), 1.2 (m, 6H).

Example 631-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}piperidinehydrochloride

White solid. Yield=29.4% m.p.=198-202° C.

¹H-NMR (CDCl₃) δ ppm: 12.4 (bs, 1H), 8.0-7.8 (m, 4H), 7.6-7.5 (m, 3H),5.7 (s, 1H), 4.75 (t, J=4.3 Hz, 2H), 3.6 (d, J=11.9 Hz, 2H), 3.4 (m,2H), 2.8 (q, J=110.0 Hz, 2H), 2.35-2.2 (m+s, 5H), 1.85 (m, 3H), 1.4 (m,1H).

Example 645-Methyl-1-(naphthalen-2-yl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolehydrochloride

White solid. Yield=10% m.p.=170-171° C.

¹H-NMR (CDCl₃) δ ppm: 12.8 (bs, 1H), 7.95-7.8 (m, 4H), 7.6-7.5 (m, 3H),5.75 (s, 1H), 4.75 (t, J=4.5 Hz, 2H), 3.9 (m, 2H), 3.5 (m, 2H), 3.0 (m,2H), 2.35 (s, 3H), 2.2 (m, 2H), 2.05 (m, 2H).

Biological Activity

Some representative compounds of the invention were tested for theiractivity as sigma (sigma-1 and sigma-2) inhibitors. The followingprotocols were followed:

Sigma-1

Brain membrane preparation and binding assays for the σ1-receptor wereperformed as described (DeHaven-Hudkins et al., 1992) with somemodifications. In brief, guinea pig brains were homogenized in 10 vols.(w/v) of Tris-HCl 50 mM 0.32 M sucrose, pH 7.4, with a KinematicaPolytron PT 3000 at 15000 r.p.m. for 30 s. The homogenate wascentrifuged at 1000 g for 10 min at 4° C. and the supernatants collectedand centrifuged again at 48000 g for 15 min at 4° C. The pellet wasresuspended in 10 volumes of Tris-HCl buffer (50 mM, pH 7.4), incubatedat 37° C. for 30 min, and centrifuged at 48000 g for 20 min at 4° C.Following this, the pellet was resuspended in fresh Tris-HCl buffer (50mM, pH 7.4) and stored on ice until use.

Each assay tube contained 10 μL of [³H](+)-pentazocine (finalconcentration of 0.5 nM), 900 μL of the tissue suspension to a finalassay volume of 1 mL and a final tissue concentration of approximately30 mg tissue net weight/mL. Non-specific binding was defined by additionof a final concentration of 1 μM haloperidol. All tubes were incubatedat 37° C. for 150 min before termination of the reaction by rapidfiltration over Schleicher & Schuell GF 3362 glass fibre filters[previously soaked in a solution of 0.5% polyethylenimine for at least 1h]. Filters were then washed with four times with 4 mL of cold Tris-HClbuffer (50 mM, pH 7.4). Following addition of scintillation cocktail,the samples were allowed to equilibrate overnight. The amount of boundradioactivity was determined by liquid scintillation spectrometry usinga Wallac Winspectral 1414 liquid scintillation counter. Proteinconcentrations were determined by the method of Lowry et al. (1951).

REFERENCES

-   DeHaven-Hudkins, D. L., L. C. Fleissner, and F. Y. Ford-Rice, 1992,    “Characterization of the binding of [³H](+)pentazocine to σ    recognition sites in guinea pig brain”, Eur. J. Pharmacol. 227,    371-378.-   Lowry, O. H., N. J. Rosebrough, A. L. Farr, and R. J. Randall, 1951,    Protein measurement with the Folin phenol reagent, J. Biol. Chem.,    193, 265.    Sigma-2

Binding studies for σ2-receptor were performed as described (Radesca etal., 1991) with some modifications. In brief, brains from sigma receptortype I (σ1) knockout mice were homogenized in a volume of 10 mL/g tissuenet weight of ice-cold 10 mM Tris-HCl, pH 7.4, containing 320 mM sucrose(Tris-sucrose buffer) with a Potter-Elvehjem homogenizer (10 strokes at500 r.p.m.) The homogenates were then centrifuged at 1000 g for 10 minat 4° C., and the supernatants were saved. The pellets were resuspendedby vortexing in 2 mL/g ice-cold Tris-sucrose buffer and centrifugedagain at 1000 g for 10 min. The combined 1000 g supernatants werecentrifuged at 31000 g for 15 min at 4° C. The pellets were resuspendedby vortexing in 3 mL/g 10 mM Tris-HCl, pH 7.4, and the suspension waskept at 25° C. for 15 min. Following centrifugation at 31000 g for 15min, the pellets were resuspended by gentle Potter Elvehjemhomogenization to a volume of 1.53 mL/g in 10 mM Tris-HCl pH 7.4.

The assay tubes contained 10 μL of [³H]-DTG (final concentration of 3nM), 400 μL of the tissue suspension (5.3 mL/g in 50 mM Tris-HCl, pH8.0) to a final assay volume of 0.5 mL. Non-specific binding was definedby addition of a final concentration of 1 μM haloperidol. All tubes wereincubated at 25° C. for 120 min before termination of the reaction byrapid filtration over Schleicher & Schuell GF 3362 glass fibre filters[previously soaked in a solution of 0.5% polyethylenimine for at least 1h]. Filters were washed with three times with 5 mL volumes of coldTris-HCl buffer (10 mM, pH 8.0). Following addition of scintillationcocktail samples were allowed to equilibrate overnight. The amount ofbound radioactivity was determined by liquid scintillation spectrometryusing a Wallac Winspectral 1414 liquid scintillation counter. Proteinconcentrations were determined by the method of Lowry et al. (1951).

REFERENCES

-   Radesca, L., W. D. Bowen, and L. Di Paolo, B. R. de Costa, 1991,    Synthesis and Receptor Binding of Enantiomeric N-Substituted    cis-N-[2-(3,4-Dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)ciclohexylamines    as High-Affinity σ Receptor Ligands, J. Med. Chem. 34, 3065-3074.-   Langa, F., Codony X., Tovar V., Lavado A., Giménez E., Cozar P.,    Cantero M., Dordal A., Hernández E., Pérez R., Monroy X., Zamanillo    D., Guitalt X., Montoliu L I., 2003, Generation and phenotypic    análisis of sigma receptor type I (Sigma1) knockout mice, European    Journal of Neuroscience, Vol. 18, 2188-2196.-   Lowry, O. H., N. J. Rosebrough, A. L. Farr, and R. J. Randall, 1951,    Protein measurement with the Folin phenol reagent, J. Biol. Chem,    193, 265.

Some of the results obtained are shown in table (I).

TABLE (I) % Binding σ1 K_(i) σ1 % Binding σ2 K_(i) σ2 Example 10⁻⁷ M nM10⁻⁶ nM nM 1 102.1 1.54 3.7 >10000 2 95.1 3 102.3 4 98.0 5 107.5 7 94.48 94.5 9 99.5 13 50.9 14 48.9 16 46.5 17 47.3 18 58.6 19 80.1 21 45.5 2297.0 2.5 23 96.4 4.4 24 110 0.5 25 94.2 3.9 27 99.2 4.1 28 95.1 30 83.031 68.6 32 72.7 33 87.1 34 103.8 12.4 35 101.7 8.6 36 52.7 37 108.5 38108.1 39 109.6 40 110.5 61 93.6 62 69.2 63 105.2 64 104.8Effect on Capsaicin in Development of Mechanical Allodynia

This model uses the von-Frey Filaments and is a model to test theeffects or symptoms of neuropathic pain, allodynia etc.

Interest of the Model:

-   -   The injection of 1 μg of capsaicin to experimental animals        produces acute pain followed by hyperalgesia/allodynia    -   The mechanisms involved in capsaicin-induced acute pain and        hyperalgesia are relatively well known (mainly activation of        peripheral nociceptors and sensitization of spinal cord neurons,        respectively)

FIG. 1 shows the test protocol for all tests with von Frey filaments.After habituation mice were according to FIG. 1 first treated with thetest-compound (or solvent in controls). Then 1 μg capsaicin (1% DMSO) isinjected into their paw resulting in developing pain in the effectedpaw. The effected paw is then treated with a mechanical stimulus and thelatency time before the paw is withdrawn is measured.

This pharmacological test showed the effect of the compound of example 1(VII) in the model described.

As shown in FIG. 2 there is a dose dependency of the treatment with thecompound of example 1 (VII) showing analgesia in capsaicin-inducedneuropathic pain.

As demonstrated in FIG. 3 the treatment with the compound of example 1(VII) is effective specifically in neuropathic pain or mechanicalallodynia shown by the force of the von-Frey filaments with 0.5 g beingtypically in the range of neuropathic pain/allodynia.

1. A compound of the formula I:

wherein R₁ is selected from the group consisting of hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted arylalkyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR₈,—C(O)OR₈, —C(O)NR₈R₉, —CH═NR₈, —CN, —OR₈, —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉,—NO₂, —N═CR₈R₉, and halogen; R₂ is selected from the group consisting ofhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉, —CH═NR₈,—CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉,and halogen; R₃ and R₄ are independently selected from the groupconsisting of hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉, —CH═NR₈,—CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉,and halogen, or together they form a fused ring system, R₅ and R₆together form, with the nitrogen atom to which they are attached, asubstituted or unsubstituted heterocyclyl group; n is 1, 2, 3, 4, 5, 6,7 or 8; t is 1, 2 or 3; R₈ and R₉ are each independently selected fromthe group consisting of hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkoxy, substituted orunsubstituted aryloxy, and halogen; or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1 wherein R₁ is H,—COR₈, or substituted or unsubstituted alkyl.
 3. The compound accordingto claim 1 wherein R₁ is hydrogen.
 4. The compound according to claim 1wherein R₂ is H or alkyl.
 5. The compound according to claim 1 whereinR₃ and R₄ are situated in the meta and para positions of the phenylgroup.
 6. The compound according to claim 1 wherein R₃ and R₄ areindependently selected from the group consisting of halogen, andsubstituted or unsubstituted alkyl.
 7. The compound according to claim 1wherein n is 2, 3, or
 4. 8. The compound according to claim 1 wherein R₅and R₆ together form a morpholine-4-yl group.
 9. A compound according toclaim 1 which is selected from the group consisting of:4-{2-(1-(3,4-dichlorophenyl)-5-methyl-1Hpyrazol-3-yloxy)ethyl}morpholine;1-(3,4-Dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;1-(3,4-Dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperidine;1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole;3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine;1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-4-methylpiperazine;Ethyl4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazinecarboxylate;1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone;4-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine;1-(4-Methoxyphenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;1-(4-Methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;1-[2-(1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidine;1-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole;4-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}morpholine;1-(3,4-Dichlorophenyl)-5-phenyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;1-(3,4-Dichlorophenyl)-5-phenyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;1-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}piperidine;1-{2-[1-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole;2-{2-[1-(3,4-dichlorophenyl)-5-phenyl-1H-pyrazol-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoquinoline;4-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}morpholine;1-(3,4-Dichlorophenyl)-5-methyl-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole;1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}piperidine;1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-4-methylpiperazine;1-{4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-1H-imidazole;1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-4-phenylpiperidine;1-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-6,7-dihydro-1H-indol-4(5H)-one;2-{4-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]butyl}-1,2,3,4-tetrahydroisoquinoline;4-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}morpholine;1-(3,4-Dichlorophenyl)-5-isopropyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;1-(3,4-Dichlorophenyl)-5-isopropyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;1-{2-[1-(3,4-Dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}piperidine;2-{2-[1-(3,4-dichlorophenyl)-5-isopropyl-1H-pyrazol-3-yloxy]ethyl}-1,2,3,4-tetrahydroisoquinoline;4-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}morpholine;1-(3,4-dichlorophenyl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;1-{2-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]ethyl}piperidine;1-(3,4-dichlorophenyl)-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazine;1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine;4-{2-[1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy]ethyl}morpholine;1-(3,4-Dichlorophenyl)-4,5-dimethyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;1-(3,4-Dichlorophenyl)-4,5-dimethyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;1-{2-[1-(3,4-Dichlorophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy]ethyl}piperidine;4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}morpholine;(2S,6R)-4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}-2,6-dimethylmorpholine;1-{4-[1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}piperidine;1-(3,4-Dichlorophenyl)-3-[4-(pyrrolidin-1-yl)butoxy]-1H-pyrazole;4-{4-[1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy]butyl}thiomorpholine;1-[1-(3,4-Dichlorophenyl)-5-methyl-3-(2-morpholinoethoxy)-1H-pyrazol-4-yl]ethanone;1-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazol-4-yl}ethanone1-{1-(3,4-dichlorophenyl)-5-methyl-3-[2-(piperidin-1-yl)ethoxy]-1H-pyrazol-4-yl}ethanone;4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine;1-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}piperidine;and5-Methyl-1-(naphthalen-2-yl)-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazoleor a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising the compound as defined in claim 1 and apharmaceutically acceptable carrier, adjuvant or vehicle.
 11. Thecompound according to claim 1 wherein R₁ is H, methyl or acetyl.
 12. Thecompound according to claim 1 wherein R₂ is methyl or H.
 13. Thecompound according to claim 1 wherein R₃ and R₄ are independentlyselected from the group consisting of halogen and haloalkyl.
 14. Thecompound according to claim 1 wherein n is 2.